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Minimizing Cardiovascular Concerns

PosttransplantAndrew D. Howard, MD, FACP

Metropolitan Nephrology AssociatesAlexandria, Virginia

Introduction• Renal transplant recipients continue to

experience improvements in short-term graft and patient survival

• Long-term outcomes have shown much slower rates of improvement

• Developments in immunosuppression which have been so critical in achieving short-term gains have likely contributed to the risk of cardiovascular disease (CVD)

• CVD remains the most important cause of mortality in renal transplant recipients

Number of Transplants And Patients on Waiting List

USRDS 2000 Annual Data Report

(113,866 as of 12/31/01)

(62,411 as of 8/20/04)

Distribution of RTR by CKD Stage

CKD= chronic kidney disease; RTR=renal transplant recipientsDjamali et.al. Kidney Intern. 2003;64:1800-1807.

05

101520253035404550

Stage 1 Stage 2 Stage 3 Stage 4

RTR (N=890)

University of Wisconsin 1985-2001

% Patients

Overall Survival Rates

CKDRTR

0102030405060708090

Kidney Survival Patient Survival

P=.25

P=<.001

Adjusted for Age, Gender and CKD Stage

CKD= chronic kidney disease; RTR=renal transplant recipientsDjamali et.al. Kidney Intern. 2003;64:1800-1807.

% Patients

Complications of CKD:Cardiovascular Disease Mortality

0.30.3 0.3 0.3 0.2 0.8

11.19.2

10.3

8.1

10.8

6.1

13.2

0.5 0.60.4 0.5 0.6

1.1

6.7

11.2

8.89.4

9.1

0.02.04.06.08.0

10.012.014.0

Total Population

Male Female White Black Diabetic

General PopulationHemodialysis PopulationPeritoneal Dialysis PopulationRenal Transplant Recipient

Adapted from Meyer KB, Levey AS. J Am Soc Nephrol. 1998;9(suppl):S31-S42.

AnnualMortality

(%)

Shlipak, M. G. et. al. Ann Intern Med. 2002;137:555-562.

Medicare beneficiaries ≥65 admitted between April 1994 – July 1995

>55 mL/min33–55 mL/min

<33 mL/min

Survival After Myocardial Infarction by Creatinine Clearance

P<.001 by log-rank test for differences

Wright, R S. et. al. Ann Intern Med. 2002;137:563-570.

P<.001

In-hospital Mortality As a Function of Creatinine Clearance

3106 consecutive patients with an acute MI at the Mayo Clinic between 1988-2000

USRDS 1998 Annual Data Report; Kidney Int 1995;47:186-193.; Kidney Int. 1999;56:2214-2219.; Ann Intern Med. 2001;134:629-636.; Arch Intern Med 2001;161:1207-1216.

Complications of CKD:Cardiovascular Disease

• Cardiovascular disease (CAD, cerebrovascular disease, PVD, CHF) more prevalent in patients with CKD than in the general population– 40% of patients have CAD or CHF at start of dialysis– Only 15% of patients have normal LV structure and

function– Framingham heart study – SCr 1.4-3.0, CVD

prevalence 18-20% vs 8-14%– HOPE study – 980 pts with 1.4 <SCr< 2.3, higher

incidence of CV death, MI, stroke– Higher incidence of traditional risk factors:DM, HTN,

hyperlipidemia, older ageCAD=coronary artery disease; CHF=congestive heart failure; CKD=chronic kidney disease; DM=diabetes mellitus; HTN=hypertension; PVD=peripheral vascular disease; SCr=serum creatinine;

K/DOQI. Am J of Kidney Dis. 2000;35:S1-S140.

Complications of CKD:Cardiovascular Disease

• Decreasing GFR & proteinuria are independent risk factors for CVD

• The relative contribution of other CKD related risk factors to CVD is highly suggestive but is not yet conclusive– RAS activity/volume overload– Abnormal Ca and Phos metabolism– Anemia– Malnutrition– Inflammation/infection– Thrombogenic factors– Oxidative stress– Homocysteine

Cause of Death in Renal Transplant Recipients

26%

7%

13% 21%

20%

13%

CerebrovasculardiseaseMyocardial infarctionOther cardiovascular

Infection

MalignancyOther

*Excludes patients whose cause of death was unknownUSRDS: 1999 Annual Data Report

CVD46%

(1995-1997)*

Cardiovascular Mortality*:RTR vs General Population

0.001

0.01

0.1

1

10

25-34 35-44 45-54 55-64 65-74 75-84Age (years)

Annu

al M

orta

lity

(%)

Renal transplantrecipients (1994-1996)

General population(1993)

*Cardiovascular mortality is underestimated in transplant recipients because of incomplete ascertainment of cause of death in these patients.Foley RN, et al. Am J Kidney Dis. 1998;32(suppl 3):S112-S119

Cardiovascular Risk Factors: General Population

1. Eckel RH. Circulation. 1997;96:3248-3250BP=blood pressure; CRP= C-reactive protein; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); TGs=triglycerides; Total-C=total cholesterol;

ConditionalRisk Factors

• TGs• Small LDL• Homocysteine• Lp(a)• Prothrombotic

factors (fibrinogen)• Inflammatory

markers (CRP)

Predisposing Risk Factors

• Obesity1

• Physical inactivity1

• Family history of premature CHD• Ethnic characteristics• Psychosocial

factors

Independent Risk Factors (Major)

• Hypertension• Diabetes mellitus• Hyperlipidemia• Smoking• Advancing age

Relative Risk for Cardiovascular Death in Renal Transplant Recipients:Cox Model

Meier-Kriesche H-U, et al. Transplantation. 2003:75;1291-1295.

< .001 1.38 – 3.03 1.67 2.2 – 2.5 < 0.001 1.25 – 1.76 1.49 1.9 – 2.1

< .001 1.85 – 2.75 2.26 2.6 – 4.0

< .001 1.16 – 1.62 1.37 1.7 – 1.8 .025 1.02 – 1.39 1.19 1.5 – 1.6 .69 0.89 – 1.20 1.03 1.3 – 1.4

Cr at 1 year < .001 1.26 – 1.81 1.51 >24 months .001 1.14 – 1.64 1.37 12–24 months .009 1.07 – 1.57 1.30 6-12 months .018 1.04 – 1.57 1.28 <6 months

ESRD Time < .001 3.26 – 4.38 3.78Diabetes < .001 1.36 – 1.92 1.61Hypertension < .001 1.049 – 1.058 1.053Age

PCIRRVariable

Classification of Blood Pressure for Adults ≥18 Years (JNC-VII)

Category SBP (mm Hg)

DBP(mm Hg)

Normal <120 And <80

Prehypertension 120-139 Or 80-89

Stage 1 HTN 140-159 Or 90-99

Stage 2 HTN 160 Or ≥ 100

JNC-VII. JAMA. 2003;289:2560-2572.

Hypertension in Renal Transplant Recipients

• Present in >95% of renal transplant recipients after 1 year (only 3.5% of patients had normal BP without medication)

• Associations with transplant-related hypertension include: – Male sex, age, diabetes & BMI– Native kidneys– Immunosuppressive agents, such as

corticosteroids and calcineurin inhibitors – Acute rejection and delayed graft function

Kasiske BL, et al. Amer J Kid Dis. 2004;6:1071-1081.

HypertensionLong Term Control Posttransplant

05

10152025303540

Normal Stage 1

1976-921993-02

JNC 7 hypertension stage at 5 years posttransplant


Pre-HTN Stage 2

%Patients

HypertensionLong Term Control Posttransplant

05

10152025303540

0 2 ≥4

Number of blood pressure medications at 5 years posttransplant


1976-921993-02

1 3

• No antihypertensive agent is absolutely contraindicated in renal transplantation

• Lifestyle modification– Sodium restriction – Weight reduction – Smoking cessation – Exercise

• Diuretics– Volume overload and hyperkalemia

• Beta-blockers– Cornerstone of therapy in CVD– Overall usage remains low & decreases with time

• Use of calcium channel blockers with appropriate adjustments in cyclosporin, tacrolimus, sirolimus

Midtvedt K, et al. Transplantation. 2001;72:1787-1792.

Treatment of Hypertension in Renal Transplant Recipients

• Reduction or elimination of corticosteroids• Reduction or conversion of cyclosporin• ACE inhibitors

– Risks: reversible decline in GFR, hyperkalemia, anemia

– Usage increasing but remains only 30% after 1 year

• Angiotensin receptor blockers – Possible decrease in production of TGF-ß– Usage ≤ 5% up to 5 years



• Goals: <130/80 mm Hg • No preferred agents• Possible options

– Diuretics• Necessary in most; choice dependent on GFR

– Beta-blockers– CCB– ACEI/ARB

• First choice for all diabetics and non-diabetics with spot protein/creatinine ≥ 200 mg/g

K/DOQI. Amer J Kid Dis. 2004;43(Suppl 1):S16-S41.

K/DOQI Clinical Practice Guidelines on HTN and antihypertensive agents in chronic kidney disease


Conversion From Cyclosporine to Tacrolimus

100

115

130

145

160

Mean Day Mean Night

Syst

olic

BP (m

m H

g)

CyclosporinFollowing conversion to tacrolimusReturn to cyclosporin

Ligtenberg G, et al. J Am Soc Nephrol. 2001;12:368-373.

**

* P<.05

Improved hypertension in stable renal transplant recipients

• An estimated 16 million individuals in the U.S. have diabetes (diagnosed + undiagnosed)

• Direct and indirect costs were estimated at $98 billion in 1997

• 25% of renal transplant recipients have preexisting diabetes (33% increase since 1992)

• 15-20 % of renal transplant recipients will develop new onset glucose intolerance after transplantation

Gaston RS, et al. Am J Kid Dis. 2004;44:529-542.

Diabetes and Renal Transplant Recipients

ADA Guidelines for Diagnosis of Diabetes

• Diabetes mellitus– FBS ≥126 mg/dL – Symptoms + casual glucose ≥200 mg/dL– 2-h postprandial glucose ≥200 mg/dL

after 75 g glucose load• Impaired fasting glucose

– FBS >100 & <126 mg/dL• Impaired glucose tolerance

– 2-h postprandial glucose ≥140 and <200 mg/dL

Diabetes Care 2003;26:S33-S50.

Posttransplant Diabetes Mellitus

• De novo development of diabetes after transplant is common, appears to be increasing in frequency and compromises patient and graft survival

• Determining the true incidence of PTDM is difficult because of variable diagnostic criteria

• Most often develops during the initial 3-6 months posttransplant but can occur at any time

• PTDM likely exerts the same adverse consequences as preexisting diabetes over 8-10 years posttransplant (CVD risk)


Incidence of PTDM Multivariate Analysis Study

Cosio FG, et al. Kidney Int. 2001;59:732-737.

Posttransplant Diabetes Mellitus:Risk Factors

• Older age of recipient• Body weight

– Risk increases with rising BMI• Ethnicity

– African American, Hispanic, Native American• Preexistent diabetes or glucose intolerance• Family history of type 2 diabetes• Hepatitis C• Dyslipidemia• Immunosuppression

– Steroids, – Calcineurin inhibitors


Diabetes Screening Posttransplant

• The American Society of Transplantation recommends posttransplant screening– Weekly for months 1-3– Every other week for months 4-6– Monthly for months 6-12 – 3-4 months thereafter

Kasiske BL, et.al. J Am Soc Nephrol. 2000;11:S1-S86.

Management After Transplantation

• Likely an expression of peripheral insulin resistance and low insulin production due to medication effect

• Complicated by the competing effects of changing renal function and diabetogenic immunosuppressants

• As renal function improves posttransplantation, insulin requirements increase

• Posttransplant infections profoundly impact therapeutic approaches to diabetes

• No superior immunosuppressive regimen exists• Provision of immunosuppression adequate to prevent

rejection and maintain allograft function is critical

Diabetes and Immunosuppressive Regimens

2.0273CsA + AZA + steroids

4.5287Prospective, randomized, parallel-group, open-label [Margreiter R, et al. Lancet. 2002;359:741-756.]

TAC + AZA + steroids

6.4328CsA + AZA + steroids6.477Posttransplant evaluation of

consecutive transplant recipients [Romagnoli J, et al. Poster abstract presented at: 2002 Congress of The Transplantation Society; August 29-30, 2002; Miami, Fl. Abstract 2104.]

TAC + steroids

4.766CsA + adjuvant agents5.7131Randomized, multicenter, open-label

[Waid T, et al. Protocol 20-98-002. IRB# 99-40118]

TAC + adjuvant agents

3.215.0

3.35.76.5

14.06.5

Incidence (%)

121*CsA + adjuvant agents245*Retrospective, multivariate,

multicenter analysis [First MR, et al. Transplantation. 2002;73:379-386.]

TAC + adjuvant agents

57*TAC + AZA46*CsA + MMF

40SIR + CNI + steroids62AZA + steroids

42*Randomized, 3-arm, parallel group, open label, prospective trial, 2000 [Johnson C, et al. Transplantation. 2000;69:834-841.]

TAC + MMF

# PatientsStudy DesignProtocol

*Number of patients not diabetic at time of transplantation

Diabetes: Long-term Treatment

• Tight glycemic control posttransplant is as important to patients with diabetes as in other settings– DCCT & UKPDS results– Results of pancreatic transplants in kidney recipients

• Metformin may be problematic• Early administration of insulin may preserve residual islet

function• HbA1c <7% checked 4 times a year• Glucose self-monitoring

– FBS 80-120 mg/dL– postprandial glucose <140-160 mg/dL

• Ophthalmologic & foot examinations• Microalbuminuria test unless frank proteinuria present

Hyperlipidemia

• Common in patients with chronic kidney disease and even more so in renal transplant recipients

• Characterized by a significant increase in – total cholesterol (>200 mg/dL)– LDL cholesterol (>130 mg/dL)– Triglycerides (>150 mg/dL)– VLDL (>35mg/dL)

• Other changes that occur in the lipid profile of the renal transplant recipient – variable effects on HDL cholesterol and Lp(a) – accumulation of atherogenic remnants (eg, IDL)

Hypercholesterolemia: Independent Risk Factor for Graft Loss

Years

010203040506070

0 1 2 3 4 5 6 7 8 9 10

% O

vera

ll Ki

dney

Gra

ft Lo

ss

Wissing KM, et al. Transplantation. 2000;70:464-472.

Acute rejection,C>250 mg/dLAcute rejection,C<250 mg/dL

Hypercholesterolemia:Risk Factor for Renal Allograft Dysfunction

Years Posttransplant

0

0.25

0.5

1 3 5 7

% P

roba

bilit

y of

Dou

blin

gSe

rum

Cre

atin

ine

Carvalho MF, et al. Clin Transplant. 2001;15:48-52.

High cholesterolNormal cholesterol

Hypertriglyceridemia:Risk Factor for Renal Allograft

Dysfunction

0

0.25

0.5

1 3 5 7Years Posttransplant

% P

roba

bilit

y of

Dou

blin

g Se

rum

Cre

atin

ine

Carvalho MF, et al. Clin Transplant. 2001;15:48-52.

High TGCNormal TGC

Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

• CHD risk equivalents – Clinical CHD– Symptomatic carotid disease– Peripheral arterial disease– Abdominal aortic aneurysm– Diabetes mellitus

• Major risk factors– Cigarette smoking– Hypertension (140/90)– HDL <40 mg/dL– Family history of early CHD– Age (men 45; women 55)

• The National Cholesterol Education Program recommendations include maintaining: – total cholesterol and LDL

cholesterol below 200 and 130 mg/dL, respectively

– HDL cholesterol above 35 mg/dL

– triglycerides below 200 mg/dL

National Cholesterol Education Program. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, Md: National Heart, Lung, and Blood Institute; 2001. NIH publication 01-3670.

KDOQI GuidelinesManagement of Dyslipidemias in Adults

With Chronic Kidney Disease

Dyslipidemia Goal Initiate Increase

TG ≥500 mg/dL

TG <500mg/dL

TLC TLC + fibrate or niacin

LDL 100-129 mg/dL

LDL <100 mg/dL

TLC TLC + low dose statin

LDL ≥130 mg/dL

LDL <100 mg/dL

TLC + low dose statin

TLC + max. dose statin

TG ≥200 & non-HDL ≥130 mg/dL

Non-HDL <130 mg/dL

TLC + low dose statin

TLC + max. dose statin

Am J Kid Dis. 2003;41(Suppl 3):S39-S58.

Lipid Lowering Agents

Increased risk of myositis/rhabdomyolysis when used with statins, cyclosporine, and tacrolimus

Myositis/rhabdomyolysis; GI upset

Fibrates

Use with cyclosporine, tacrolimus, and prednisone may exacerbate glucose intolerance

Glucose intolerance; increased LFTs

Nicotinic acid

May interfere with cyclosporine and tacrolimus absorption

May cause bloating/constipation

Bile acid resin

Interactions With Immunosuppressives

Side Effects

LFT = liver function test; GI = gastrointestinal.

Lipid Lowering Agents

Interactions With Immunosuppressives

Side Effects

Increased risk of myositis/rhabdomyolysis when used with fibrates, cyclosporine, and tacrolimus

Myositis/rhabdomyolysis; increased LFTs; GI upset

Statins (HMG-CoA reductase inhibitors)

Cyclosporin may increase levels

Angioedema, diarrhea, abdominal pain

Ezitimibe

Treatment for Hyperlipidemia in Renal Transplant Recipients

• Diet– Saturated fat: < 7% of total calories– Polyunsaturated fat: up to 10% of total

calories– Monounsaturated fat: up to 20% of total

calories– Total fat: 25-35% of total calories– Complex carbohydrates: 50-60% of total

calories– Fiber: 20-30 g/day– Cholesterol: < 200 mg/day

Am J Kid Dis ;41(Suppl 3):S39-S58.


• BMI– 25-28 kg/m2

• Moderate physical activity– 20-30 minutes 3-4 x/week

• Alcohol in moderation• Smoking cessation

Am J Kid Dis 41(Suppl 3):S39-S58.


• Statins are the drugs of choice to lower LDL cholesterol– Begin with lower doses if on therapy

with a CNI (esp CYA, ?TAC)– No data on SRL

• Use caution if adding a fibrate and begin with reduced dosages with GFR <90 unless using gemfibrozil

Am J Kid Dis 41(Suppl 3):S39-S58.


• If LDL remains ≥100 mg/dL despite maximal medical management, consider– Tapering or discontinuing prednisone +/-

adding or increasing the dose of AZA or MMF– Tapering or discontinuing CYA +/- adding or

decreasing the dose of AZA or MMF– Replacing CYA with TAC– Discontinuing or replacing SRL

• Bile acid sequestrants may interfere with the absorption of immunosuppressive agents (CNI)

Hyperlipidemia: Post-Hoc Subgroup Analysis of the ALERT Study

• 2102 renal transplant patients treated with fluvastatin (40-80 mg) for 5-6 years

• 32 % reduction in LDL cholesterol vs placebo• Incidence of cardiac death or nonfatal MI

reduced from 104 to 70 events vs placebo (RR 0.65, P=.005)

• Statistically significant in multiple subgroups including patients at lower CV risk

Jardine AG, et.al. Am J Trans. 2004;4:988-995.

Use of Lipid Reducing Drugs Over Time—Tacrolimus vs Cyclosporine

Vincenti F, et al. Transplantation. 2002;73:775-782.

0

10

20

30

40

50

60

90 Days 1 Year 3 Years 5 Years

% P

atie

nts

P=NS P <.05 P <.05 P <.001

TacrolimusCyclosporin

Hypercholesterolemia After Conversion to Tacrolimus

McCune TR, et al. Transplantation. 1998;65:87-92

0

50

100

150

200

250

300

Cholesterol LDL Cholesterol Apolipoprotein B

Seru

m L

ipid

Lev

els (

mg/

dL)

P=.0005 P=.0007 P=.0098

TacrolimusCyclosporin

Hyperhomocysteinemia• Common condition in renal transplant

recipients • Testing for fasting homocysteine level might be

a useful tool to identify patients at increased risk for development of vascular disease

• Further long-term studies are needed to determine the best treatment

• Effects of immunosuppressive therapy on hyperhomocysteinemia are also under investigation

Cardiovascular Risks Associated With Immunosuppressive Regimens

++++Sirolimus (SRL)+++Tacrolimus (TAC)

+++++Cyclosporin (CYA)

++++++++AZA or MMF + Pred + CYA

+++++Prednisone (Pred)

+++++++

Diabetes

++++++SRL + Pred + CYA+++++SRL + Pred + TAC

+++AZA or MMF + Pred + TAC

MMF + Pred + SRL

Azathioprine (AZA) or MMFImmunosuppressant

++++

HyperlipidemiaHypertension

MMF = mycophenolate mofetil, + = least association, ++++ = greatest association.

Conclusion• Cardiovascular disease after renal

transplantation is related to a high prevalence and accumulation of risk factors before and after transplantation

• Hypertension, diabetes and hyperlipidemia are well-recognized risk factors and are linked to immunosuppressive therapy

• Reducing cardiovascular risk can only be accomplished by reducing the impact of these defined risk factors early after the onset of chronic kidney disease and effectively after renal transplantation

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